The bones of the skeleton are not entirely solid throughout. The outside, i.e., cortical, bone is substantially solid, having only a few small (Haversian) canals. Located inwardly from the cortical bone, however, is spongy bone known as cancellous (or trabecular) bone. The cancellous bone is composed of a honeycomb network of trabecular bone defining a plurality of spaces or cavities filled with fluid bone marrow, stem cells and some fat cells. Existing within these bone marrow cavities are, inter alia, various highly specialized cells which assist in breaking down existing bone (i.e., osteoclasts) as well as cells that correspondingly produce new bone (i.e., osteoblasts) to replace that which is broken down or which may be otherwise lost due to factors such as injury or illness.
As indicated above, the physical structure of bone may be compromised for a variety of reasons, including injury and disease. One of the most common bone diseases is osteoporosis, which is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and increased susceptibility to fractures, particularly of the hip, spine and wrist. Osteoporosis develops where there is an imbalance such that the rate of bone resorption exceeds the rate of bone formation. This is, in part, due to the fact that it can require six months for osteoblasts to rebuild the amount of bone destroyed by osteoclasts in three days. By age fifty-five, for example, the average woman with osteoporosis has already lost thirty percent of her bone mass.
Osteoporosis is drastically accelerated during menopause and is the third leading cause of death of women over seventy. The disease also afflicts men, who account for twenty percent of all osteoporosis sufferers. By the age of seventy-five, approximately ninety percent of all women and thirty-three percent of all men will suffer from osteoporosis. The ailment causes 1.5 million fractures a year, resulting in annual U.S. health care costs exceeding $18 billion. One in two women and one in eight men over age fifty will have an osteoporosis-related fracture in their lifetime. Of those who suffer from hip fractures, one in five will not survive more than one year. Currently, less than ten percent of afflicted persons are treated for osteoporosis with prescription drugs.
Such prescription drugs typically include at least one bone augmentation agent. A ‘bone augmentation agent’, as that term is used herein, includes but is not limited to bone anabolic agents, and agents that cause elevated blood levels of an endogenous bone anabolic agent to be produced within a subject. Bone augmentation agents, such as bone anabolic agents, are well known in the art. Bone anabolic agents commonly include (but are not limited to) parathyroid hormone and various parathyroid hormone fragments, whether amidated or in the free acid form, as well as PTHrP and analogues thereof, Prostaglandin E-2, Bone Morphogenic Proteins, IGF-1, Growth Hormone, fibroblast growth factor TGF and others. On the other hand, agents causing increased expression of endogenous bone anabolic agent include, but again are not limited to, calcilytic agents as well as antibodies to sclerostin. Calcilytic agents typically, but not necessarily, include agents that limit the binding of calcium to its receptor, thereby triggering the release of endogenous parathyroid hormone. Examples of these materials are set forth in U.S. Pat. Nos. 6,362,231; 6,395,919; 6,432,656 and 6,521,667, the contents of which are expressly incorporated herein by reference.
Reliance upon the administration of bone augmentation agents such as those described above, for the purpose of, e.g., increasing bone density, however, frequently involves lengthy treatment regimens with accompanying patient compliance problems. Additionally, such treatment produces a systemic effect which targets the entire skeletal system and thus, it is not and can not be ‘targeted’ to create an effect in one or more specific bone(s).
In order, therefore, to provide a faster and more targeted method of inducing bone formation in subjects suffering from, e.g., diminished bone mass, and for aiding in preserving the retention of the new bone growth so produced, several of the co-inventors of the present invention have developed a method for fostering bone formation and preservation which overcomes the deficiencies noted above of the prior art. The method comprises the steps of mechanically inducing an increase in osteoblast activity in one or more ‘targeted’ bones of a subject in need of additional bone growth, coupled with elevating blood concentration of at least one bone anabolic agent in the subject, wherein the above steps may be performed in any order but wherein they are carried out in sufficient time proximity that the elevated concentration of the bone anabolic agent and the mechanically induced increase in osteoblast activity at least partially overlaps. The above methodology is described, for example, in U.S. patent application Ser. No. 11/128,095 file May 11, 2005 and in U.S. continuation-in-part patent application Ser. No. 11/267,987 filed Nov. 7, 2005. The contents of both of these applications are incorporated herein by reference. As indicated above, the method permits specific targeting of particular bones for effects such as repair, strengthening, reshaping and/or remodeling.
Although the above-described method has been found to be particularly effective in growing and preserving new bone when the area targeted for such additional bone growth is provided with a sufficient amount of cancellous bone to serve as a scaffold for supporting the new growth, it has now been determined that the new bone produced by the action of the bone anabolic agent alone, whether such agent is endogenous or otherwise, may not be ideal for replacement of bone in regions which lack sufficient cancellous bone to serve as a scaffold. Furthermore, the use of PTH and other anabolics may not be efficient at filling gaps in trabeculae that are perforated due to increased bone resorption. Over time, some of the bone produced via augmentation agents (including but not limited to anabolic agents) may be lost via such resorption in those areas, as noted above, lacking the bony scaffolding. Previous efforts to prevent, or at least minimize such resorption, have involved the administration of anti-resorptive agents, which are well-known in the art. These agents include (but are not limited to) calcitonins including, for example, human calcitonin, salmon calcitonin, eel calcitonin, elkatonin, porcine calcitonin, chicken calcitonin, SERMS (Selective Estrogen Receptor Modulators), Bisphosphonates, Strontium Ranelate and combinations thereof. Such administration of an antiresorptive agent is able to protect the newly formed bone. However, some or all of the new bone formed during the initial growth ‘spurt’ facilitated due to the presence of the anabolic agent, may nevertheless be resorbed by the subject. Thus, the effectiveness of the new bone, such as increased skeletal strength and/or support, will be compromised.
It has been discovered, however, by the present inventors that the addition of a biocompatible matrix-forming material in these specific areas will prevent the new targeted bone from being lost since it will serve as a support permitting additional bone growth. In addition, the installation of such a biocompatible matrix has been found to better enable bone to be synthesized in regions such as the area within the shaft of a long bone, e.g., the humerus.
For purposes of illustration, one particular location where bone thinning and resultant bone damage, including fracturing, attributable to such thinning is problematic is in the vertebrae of the spine. Vertebroplasty and kyphoplasty, which are currently in common use in the United States, are surgical procedures for vertebral augmentation that also treat pain associated with vertebral compression fractures. Both of these procedures use x-ray guidance and a transpedicular or parapedicular technique to access the vertebral body for injecting liquid cement therein. The cement then solidifies to augment the weakened and painful vertebra. The simplest procedure is vertebroplasty. This technique is discussed, for example, in U.S. Pat. No. 6,273,916, the contents of which are incorporated herein by reference. A more recent procedure, becoming more common, is kyphoplasty which involves the inflation of a balloon to restore height, whereupon a bone cement is injected into the cavity created by the balloon.
A highly popular bone cement for use in these procedures is polymethyl methacrylate (“PMMA”). The use of PMMA is described in a variety of professional journal articles, including: (a) “Is Percutaneous Vertebroplasty without Pretreatment Venography Safe? Evaluation of 205 Consecutive Procedures”, Cristiana Vasconcelos, Philippe Gailloud, Norman J. Beauchamp, Donald V. Heck, and Kieran J. Murphy, AJNR Am J Neuroradiol 23:913-917, June/July 2002 (“Vasconcelos”); (b) “Bone Cements: Review of Their Physiochemical and Biochemical Properties in Percutaneous Vertebroplasty”, Matthew J. Provenzano, Kieran P. J. Murphy, and Lee H. Riley III, AJNR Am J Neuroradiol 25:1286-1290, August 2004 (“Provenzano”); (c) “The Chemistry of Acrylic Bone Cements and Implications for Clinical Use in Image-Guided Therapy”, David A. Nussbaum, M S, Philippe Gailloud, Md., and Kieran Murphy, Md., J Vasc Interv Radiol 2004; 15 Page 1. (“Nussbaum”). The contents of each of these papers is incorporated herein by reference.
PMMA is an acrylic bone cement. It is not adhesive and it does not integrate into bone over time, and yet it is remarkably strong. As an analogy, PMMA can act like rebar in cement as used in building construction. The use of PMMA does offer a significant drawback, however, in that PMMA is known to remove or reduce forces that maintain bone density by supplanting the role of trabecular bone structure in its neighborhood, thus removing or reducing the electrical charge that contributes to bone development.
Furthermore, the monomer liquid used to dissolve the PMMA powder can be toxic and has been associated with complications such as death and cardiac arrest (See the Nussbaum article). The high compressive strength of PMMA can, in addition, cause adjacent vertebral body fractures by exerting high non compliant forces on the adjacent vertebra, as the vertebral body is too stiff as a result of the injection of the PMMA. These adjacent fractures occur between eight and ten percent of the time.
A promising alternative to PMMA are biologically active bone cements or biocompatible polymers. Biologically active bone matrices can obviate some of the difficulties encountered with the use of PMMA. For example, biologically active bone cements can be of lower strength than PMMA, thus causing less stiffness of the vertebral body when they are injected. However, there are a number of problems inherent in their use in, for example, vertebral augmentation. For example, biologically active bone cements are very difficult to inject, they lack natural radio density, and they do not always integrate well for months or even years. Further, some biologically active bone cements require hours before they solidify and become safe. More generally, there have been deaths from the use of some of these cements, which may be related to the pH from the cement injected or the leaking of calcium into the circulation, resulting in disseminated clotting. There is currently little knowledge, however, of how to use biologically active bone cement for vertebral augmentation procedures.
A biologically active cement useful in vertebral augmentation is calcium phosphate. Calcium phosphate cements are composed of a powder and a liquid solution that dissolves the powder. They are used widely in hip, spine and wrist surgery and also in cranial restriction. There are two different families of calcium phosphate cements. One group undergoes an exothermic reaction while another undergoes an endothermic reaction. One group belongs to a family called bruschite cements. The other group belongs to a family that ultimately forms hydroxy apatite, the precursor of bone. When calcium phosphate powders and the aqueous solution are mixed, a paste is formed which sets within minutes to hours. Thus, they are often poorly injectable and poorly visualized under x-ray guidance, making them difficult to use for vertebral augmentation procedures. Further, when they are delivered into the bone, they are acted upon by osteoblasts and osteoclasts in the residual trabecular bone structure. If there is no residual trabecular bone structure the peripheral bone cement may be integrated at the endosteal surface of the bone, but bone cement located within the mass of the vertebral body may remain in its unchanged form, a brittle ceramic of low tensile and compressive strength with potential long term negative consequences.
In view of the deficiencies noted above of the prior art, there has been a long-felt need by those working in this field for a faster and more effective method of inducing bone formation in bones lacking a bony scaffolding comprised of trabecular bone, coupled with an enhancement in the degree of retention of the new bone thus produced. The present invention, in the manner set forth below, admirably fulfills these desired functions.